The effect of CO2 on the age dependence of neurovascular coupling.

Prior studies have identified variable effects of healthy aging on neurovascular coupling (NVC). Carbon dioxide (CO2) affects both cerebral blood velocity (CBv) and NVC, but the effects of age on NVC under different CO2 conditions are unknown. Therefore, we investigated the effects of aging on NVC in different CO2 states in healthy controls during cognitive paradigms. 78 healthy participants (18-78 years) underwent continuous recordings of CBv by bilateral insonation of middle (MCA) and posterior (PCA) cerebral arteries (transcranial Doppler), blood pressure, end-tidal CO2, and heart rate during poikilocapnia, hypercapnia (5% CO2 inhalation) and hypocapnia (paced hyperventilation). Neuroactivation via visuospatial (VS) and attention tasks (AT) augmented CBv. Peak percentage change in MCAv/PCAv, were compared between CO2 conditions and age groups (< 30, 31-60, and >60 years). For the VS task, in normocapnia, younger adults had a lower NVC response compared to older adults (mean difference (MD): -7.92% (standard deviation (SD): 2.37), p=0.004), but comparable between younger and middle-aged groups. In hypercapnia, both younger (MD: -4.75% (SD: 1.56), p=0.009) and middle (MD: -4.58% (SD: 1.69), p=0.023) age groups had lower NVC responses compared to older adults. Finally, in hypocapnia, both older (MD: 5.92% (SD: 2.21), p=0.025) and middle (MD: 5.44% (SD: 2.27), p=0.049) age groups had greater NVC responses, compared to younger adults. In conclusion, the middle-aged adults demonstrated a variable NVC response, comparable to younger adults under hypercapnia, and older adults under hypocapnia. This may owe to a more cognitively favourable profile while under hypercapnic conditions, compared to hypocapnia.

Determinants of the dynamic cerebral critical closing pressure response to changes in mean arterial pressure.

Objective. Cerebral critical closing pressure (CrCP) represents the value of arterial blood pressure (BP) where cerebral blood flow (CBF) becomes zero. Its dynamic response to a step change in mean BP (MAP) has been shown to reflect CBF autoregulation, but robust methods for its estimation are lacking. We aim to improve the quality of estimates of the CrCP dynamic response.Approach. Retrospective analysis of 437 healthy subjects (aged 18-87 years, 218 males) baseline recordings with measurements of cerebral blood velocity in the middle cerebral artery (MCAv, transcranial Doppler), non-invasive arterial BP (Finometer) and end-tidal CO2(EtCO2, capnography). For each cardiac cycle CrCP was estimated from the instantaneous MCAv-BP relationship. Transfer function analysis of the MAP and MCAv (MAP-MCAv) and CrCP (MAP-CrCP) allowed estimation of the corresponding step responses (SR) to changes in MAP, with the output in MCAv (SRVMCAv) representing the autoregulation index (ARI), ranging from 0 to 9. Four main parameters were considered as potential determinants of the SRVCrCPtemporal pattern, including the coherence function, MAP spectral power and the reconstruction error for SRVMAP, from the other three separate SRs.Main results. The reconstruction error for SRVMAPwas the main determinant of SRVCrCPsignal quality, by removing the largest number of outliers (Grubbs test) compared to the other three parameters. SRVCrCPshowed highly significant (p< 0.001) changes with time, but its amplitude or temporal pattern was not influenced by sex or age. The main physiological determinants of SRVCrCPwere the ARI and the mean CrCP for the entire 5 min baseline period. The early phase (2-3 s) of SRVCrCPresponse was influenced by heart rate whereas the late phase (10-14 s) was influenced by diastolic BP.Significance. These results should allow better planning and quality of future research and clinical trials of novel metrics of CBF regulation.

Depression of dynamic cerebral autoregulation during neural activation: The role of responders and non-responders.

Neurovascular coupling (NVC) interaction with dynamic cerebral autoregulation (dCA) remains unclear. We investigated the effect of task complexity and duration on the interaction with dCA. Sixteen healthy participants (31.6 ± 11.6 years) performed verbal fluency (naming-words (NW)) and serial subtraction (SS) paradigms, of varying complexity, at durations of 05, 30 and 60 s. The autoregulation index (ARI), was estimated from the bilateral middle cerebral artery blood velocity (MCAv) step response, calculated by transfer function analysis (TFA), for each paradigm during unstimulated (2 min) and neuroactivated (1 min) segments. Intraclass correlation (ICC) and coefficient of variation (CV) determined reproducibility for two visits and objective criteria were applied to classify responders (R) and non-responders (NoR) to task-induced MCAv increase. ICC values demonstrated fair reproducibility in all tasks. ARI decreased in right (RH) and left (LH) hemispheres, irrespective of paradigm complexity and duration (p < 0.0001). Bilateral ARI estimates were significantly decreased during NW for the R group only (p < 0.0001) but were reduced in both R (p < 0.0001) and NoR (p = 0.03) groups for SS tasks compared with baseline. The reproducible attenuation of dCA efficiency due to paradigm-induced NVC response, its interaction, and different behaviour in R and NoR, warrant further research in different physiological and clinical conditions.

Tratamiento antiagregante plaquetario oral para el ictus isquémico agudo: una revisión Cochrane / Oral antiplatelet therapy for acute ischaemic stroke: a Cochrane review

Pregunta de la revisión. Queríamos comparar la seguridad y la eficacia del tratamiento antiplaquetario oral frente a placebo o ningún tratamiento en personas con ictus isquémico agudo para ver si los antiplaquetarios orales reducían el número de muertes y mejoraban los resultados a largo plazo en los supervivientes. Fundamento. La mayoría de los ictus están causados por una obstrucción repentina de una arteria del cerebro que suele deberse a un coágulo de sangre (lo que se denomina ictus isquémico). El tratamiento inmediato con antiagregantes plaquetarios, como la aspirina, puede evitar la formación de nuevos coágulos y mejorar así la recuperación tras el ictus. Sin embargo, los antiagregantes plaquetarios también pueden provocar hemorragias cerebrales, lo que podría anular sus efectos beneficiosos. Características del estudio. Se identificaron 11 estudios, hasta agosto de 2020, para su inclusión en la revisión. Estos estudios incluyeron 42.226 participantes. Tres eran nuevos ensayos desde la última actualización. Como en la versión anterior de esta revisión, dos estudios aportaron el 96% de los datos. La mayoría de los participantes en la revisión eran ancianos, con una proporción significativa de más de 70 años. Los hombres y las mujeres estaban representados casi por igual en los ensayos. Parecía haber alguna variación en la gravedad del accidente cerebrovascular entre los ensayos incluidos. La duración programada del tratamiento varió de 5 días a 3 meses y el periodo de seguimiento programado varió de 10 días a 6 meses. Resultados clave. La aspirina, en dosis de 160 mg a 300 mg diarios, iniciada en las 48 horas siguientes a la aparición de los síntomas del ictus, salvó vidas y redujo el riesgo de que se produjera un nuevo ictus en las dos primeras semanas... (AU)

Tratamiento antiagregante plaquetario oral para el ictus isquémico agudo: una revisión Cochrane / Oral antiplatelet therapy for acute ischaemic stroke: a Cochrane review

Pregunta de la revisión. Queríamos comparar la seguridad y la eficacia del tratamiento antiplaquetario oral frente a placebo o ningún tratamiento en personas con ictus isquémico agudo para ver si los antiplaquetarios orales reducían el número de muertes y mejoraban los resultados a largo plazo en los supervivientes. Fundamento. La mayoría de los ictus están causados por una obstrucción repentina de una arteria del cerebro que suele deberse a un coágulo de sangre (lo que se denomina ictus isquémico). El tratamiento inmediato con antiagregantes plaquetarios, como la aspirina, puede evitar la formación de nuevos coágulos y mejorar así la recuperación tras el ictus. Sin embargo, los antiagregantes plaquetarios también pueden provocar hemorragias cerebrales, lo que podría anular sus efectos beneficiosos. Características del estudio. Se identificaron 11 estudios, hasta agosto de 2020, para su inclusión en la revisión. Estos estudios incluyeron 42.226 participantes. Tres eran nuevos ensayos desde la última actualización. Como en la versión anterior de esta revisión, dos estudios aportaron el 96% de los datos. La mayoría de los participantes en la revisión eran ancianos, con una proporción significativa de más de 70 años. Los hombres y las mujeres estaban representados casi por igual en los ensayos. Parecía haber alguna variación en la gravedad del accidente cerebrovascular entre los ensayos incluidos. La duración programada del tratamiento varió de 5 días a 3 meses y el periodo de seguimiento programado varió de 10 días a 6 meses. Resultados clave. La aspirina, en dosis de 160 mg a 300 mg diarios, iniciada en las 48 horas siguientes a la aparición de los síntomas del ictus, salvó vidas y redujo el riesgo de que se produjera un nuevo ictus en las dos primeras semanas... (AU)

The effect of hypercapnia on the directional sensitivity of dynamic cerebral autoregulation and the influence of age and sex.

The cerebral circulation responds differently to increases in mean arterial pressure (MAP), compared to reductions in MAP. We tested the hypothesis that this directional sensitivity is reduced by hypercapnia. Retrospective analysis of 104 healthy subjects (46 male (44%), age range 19-74 years), with five minute recordings of middle cerebral blood velocity (MCAv, transcranial Doppler), non-invasive MAP (Finometer) and end-tidal CO2 (capnography) at rest, during both poikilocapnia and hypercapnia (5% CO2 breathing in air) produced MCAv step responses allowing estimation of the classical Autoregulation Index (ARIORIG), and corresponding values for both positive (ARI+D) and negative (ARI-D) changes in MAP. Hypercapnia led to marked reductions in ARIORIG, ARI+D and ARI-D (p < 0.0001, all cases). Females had a lower value of ARIORIG compared to males (p = 0.030) at poikilocapnia (4.44 ± 1.74 vs 4.74 ± 1.48) and hypercapnia (2.44 ± 1.93 vs 3.33 ± 1.61). The strength of directional sensitivity (ARI+D-ARI-D) was not influenced by hypercapnia (p = 0.46), sex (p = 0.76) or age (p = 0.61). During poikilocapnia, ARI+D decreased with age in females (p = 0.027), but not in males. Directional sensitivity was not affected by hypercapnia, suggesting that its origins are more likely to be inherent to the mechanics of vascular smooth muscle than to myogenic pathways.

Dynamic cerebral autoregulation in Alzheimer's disease and mild cognitive impairment: A systematic review.

Dynamic cerebral autoregulation (dCA) is a key mechanism that regulates cerebral blood flow (CBF) in response to transient changes in blood pressure (BP). Impairment of dCA could increase vulnerability to hypertensive vascular damage, but also to BP lowering effects of antihypertensive treatment. The literature remains conflicted on whether dCA is altered in Alzheimer's disease (AD) and mild cognitive impairment (MCI). We summarized available data on dCA in AD and MCI, by searching PubMed, Embase, PsycINFO and Web of Science databases (inception-January 2022). Eight studies (total n = 443) were included in the qualitative synthesis of which seven were eligible for meta-analysis. All studies used Transcranial Doppler (TCD) ultrasonography and transfer function analysis or the autoregulatory index to assess dCA during spontaneous or induced BP fluctuations. Meta-analysis indicated no significant difference between AD, MCI and healthy controls in dCA parameters for spontaneous fluctuations. For induced fluctuations, the available data were limited, but indicative of at least preserved and possibly better autoregulatory functioning in AD and MCI compared to controls. In summary, current evidence does not suggest poorer dCA efficiency in AD or MCI. Further work is needed to investigate dCA in dementia with induced fluctuations controlling for changes in end-tidal carbon dioxide.

The role of the autonomic nervous system in cerebral blood flow regulation in stroke: A review.

Stroke is a pathophysiological condition which results in alterations in cerebral blood flow (CBF). The mechanism by which the brain maintains adequate CBF in presence of fluctuating cerebral perfusion pressure (CPP) is known as cerebral autoregulation (CA). Disturbances in CA may be influenced by a number of physiological pathways including the autonomic nervous system (ANS). The cerebrovascular system is innervated by adrenergic and cholinergic nerve fibers. The role of the ANS in regulating CBF is widely disputed owing to several factors including the complexity of the ANS and cerebrovascular interactions, limitations to measurements, variation in methods to assess the ANS in relation to CBF as well as experimental approaches that can or cannot provide insight into the sympathetic control of CBF. CA is known to be impaired in stroke however the number of studies investigating the mechanisms by which this occurs are limited. This literature review will focus on highlighting the assessment of the ANS and CBF via indices derived from the analyses of heart rate variability (HRV), and baroreflex sensitivity (BRS), and providing a summary of both clinical and animal model studies investigating the role of the ANS in influencing CA in stroke. Understanding the mechanisms by which the ANS influences CBF in stroke patients may provide the foundation for novel therapeutic approaches to improve functional outcomes in stroke patients.

Challenging neurovascular coupling through complex and variable duration cognitive paradigms: A subcomponent analysis.

A similar pattern of cerebral blood velocity (CBv) response has been observed for neurovascular coupling (NVC) assessment with cognitive tasks of varying complexity and duration. This lack of specificity could result from parallel changes in arterial blood pressure (BP) and PaCO2, which could confound the estimates of NVC integrity. Healthy participants (n = 16) underwent recordings at rest (5 min sitting) and during randomized paradigms of different complexity (naming words (NW) beginning with P-, R-, V- words and serial subtractions (SS) of 100-2, 100-7, 1000-17, with durations of 5, 30 and 60 s). Bilateral CBv (middle cerebral arteries, transcranial Doppler), end-tidal CO2 (EtCO2, capnography), blood pressure (BP, Finapres) and heart rate (HR, ECG) were recorded continuously. The bilateral CBv response to all paradigms was classified under objective criteria to select only responders, then the repeated data were averaged between visits. Bilateral CBv change to tasks was decomposed into the relative contributions (subcomponents) of arterial BP (VBP; neurogenic), critical closing pressure (VCrCP; metabolic) and resistance area product (VRAP; myogenic). A temporal effect was demonstrated in bilateral VBP and VRAP during all tasks (p<0.002), increased VBP early (between 0 and 10 s) and followed by decreases of VRAP late (25-35 s) in the response. VCrCP varied by complexity and duration (p<0.046). The main contributions to CBv responses to cognitive tasks of different complexity and duration were VBP and VRAP, whilst a smaller contribution from VCrCP would suggest sensitivity to metabolic demands. Further studies are needed to assess the influence of different paradigms, ageing and cerebrovascular conditions.

The role of the autonomic nervous system in cerebral blood flow regulation in dementia: A review.

In this review we will examine the role of the autonomic nervous system in the control of cerebral blood flow (CBF) in dementia. Worldwide, 55 million people currently live with dementia, and this figure will increase as the global population ages. Understanding the changes in vascular physiology in dementia could pave the way for novel therapeutic approaches. Reductions in CBF have been demonstrated in multiple dementia sub-types, in addition to increased cerebrovascular resistance and reduced vasoreactivity. Cerebral autoregulation (CA) is a key mechanism for the maintenance of cerebral perfusion, but remains largely intact in cognitive disorders, despite reductions in global and regional CBF. However, the tight coupling between neuronal activity and CBF (neurovascular coupling - NVC) is lost in dementia, which may be a key driver of cognitive dysfunction. Despite numerous studies investigating disturbances in the control of CBF in dementia, less is known about the specific mechanisms responsible for the observed changes. Disturbances could be related to one of a number of pathways and mechanisms including disruption of the autonomic component. In this review we will explore clinical and animal studies, which specifically investigated the autonomic component of CBF control in dementia, drawing on the clinical implications and potential for novel biomarker and therapeutic targets.

The Cognition and Flow Study (CogFlowS): A Mixed Method Evaluation of a Randomized Feasibility Trial of Cognitive Training in Dementia.

BACKGROUND: Cognitive training (CT) may be beneficial in delaying the onset or slowing dementia progression. CT has been evaluated quantitatively and qualitatively, but none have used mixed methods approaches. OBJECTIVE: The aim of this study was to use a mixed methods approach to identify those who may selectively benefit from CT. METHODS: This was an explanatory sequential mixed methods study involving a quantitative randomized trial of 12 weeks multi-domain CT in healthy older adults (HC, n = 20), and people living with mild cognitive impairment (MCI; n = 12) and dementia (n = 24). Quantitative outcomes included: cognition, mood, quality of life, and activities of daily living. 28 (10 HC, 6 MCI, 12 dementia) training participants completed semi-structured interviews with their carer. Quantitative and qualitative data were integrated using joint displays. RESULTS: Three participants dropped out from the training early-on, leaving 25 participants with follow-up data for full integration (10 HC, 6 MCI, 9 dementia). Dropouts and lower adherence to training were more common in dementia participants with greater non-modifiable barriers. High adherers were more resilient to negative emotions, and poorer or fluctuating performance. Integrated analysis found the majority of participants (n = 24) benefited across outcomes, with no clear profile of individuals who benefited more than others. Participants made a number of key recommendations to improve adherence and minimize dropout to CT. CONCLUSION: Reasons for dropout and low adherence were identified, with recommendations provided for the design of CT for dementia. An individual approach to training should be adopted and low adherence should not preclude engagement with CT.

Diagnostic test accuracy of remote, multidomain cognitive assessment (telephone and video call) for dementia.

BACKGROUND: Remote cognitive assessments are increasingly needed to assist in the detection of cognitive disorders, but the diagnostic accuracy of telephone- and video-based cognitive screening remains unclear. OBJECTIVES: To assess the test accuracy of any multidomain cognitive test delivered remotely for the diagnosis of any form of dementia. To assess for potential differences in cognitive test scoring when using a remote platform, and where a remote screener was compared to the equivalent face-to-face test. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, LILACS, and ClinicalTrials.gov (www. CLINICALTRIALS: gov/) databases on 2 June 2021. We performed forward and backward searching of included citations. SELECTION CRITERIA: We included cross-sectional studies, where a remote, multidomain assessment was administered alongside a clinical diagnosis of dementia or equivalent face-to-face test. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data; a third review author moderated disagreements. Our primary analysis was the accuracy of remote assessments against a clinical diagnosis of dementia. Where data were available, we reported test accuracy as sensitivity and specificity. We did not perform quantitative meta-analysis as there were too few studies at individual test level. For those studies comparing remote versus in-person use of an equivalent screening test, if data allowed, we described correlations, reliability, differences in scores and the proportion classified as having cognitive impairment for each test. MAIN RESULTS: The review contains 31 studies (19 differing tests, 3075 participants), of which seven studies (six telephone, one video call, 756 participants) were relevant to our primary objective of describing test accuracy against a clinical diagnosis of dementia. All studies were at unclear or high risk of bias in at least one domain, but were low risk in applicability to the review question. Overall, sensitivity of remote tools varied with values between 26% and 100%, and specificity between 65% and 100%, with no clearly superior test. Across the 24 papers comparing equivalent remote and in-person tests (14 telephone, 10 video call), agreement between tests was good, but rarely perfect (correlation coefficient range: 0.48 to 0.98). AUTHORS' CONCLUSIONS: Despite the common and increasing use of remote cognitive assessment, supporting evidence on test accuracy is limited. Available data do not allow us to suggest a preferred test. Remote testing is complex, and this is reflected in the heterogeneity seen in tests used, their application, and their analysis. More research is needed to describe accuracy of contemporary approaches to remote cognitive assessment. While data comparing remote and in-person use of a test were reassuring, thresholds and scoring rules derived from in-person testing may not be applicable when the equivalent test is adapted for remote use.

Effect of Antihypertensive Treatment on Cerebral Blood Flow in Older Adults: a Systematic Review and Meta-Analysis.

BACKGROUND: In older age, the benefits of antihypertensive treatment (AHT) become less evident, with greater associated risk. Of particular concern is compromising cerebral blood flow (CBF), especially in those with cognitive impairment. METHODS: We created a synthesis of the published evidence by searching multiple electronic databases from 1970 to May 2021. Included studies had participants with mean age ≥50 years, hypertension or cognitive impairment, and assessed CBF before and after initiating AHT. Two authors independently determined eligibility and extracted data. Study quality was assessed using The Risk of Bias in Nonrandomized Studies of Interventions tool. We summarized study characteristics (qualitative synthesis) and performed random-effects meta-analyses (quantitative synthesis). RESULTS: Thirty-two studies (total n=1306) were included, of which 23 were eligible for meta-analysis. In line with the qualitative synthesis, the meta-analysis indicated no effect of AHT initiation on CBF (standardized mean difference, 0.08 [95% CI, -0.07 to 0.22]; P=0.31, I2=42%). This was consistent across subgroups of acute versus chronic AHT, drug class, study design, and CBF measurement. Subgroups by age demonstrated an increase in CBF after AHT in those aged >70 years (standardized mean difference, 4.15 [95% CI, 0.16-8.15]; P=0.04, I2=42%), but not in those aged 50 to 65 and 65 to 70 years (standardized mean difference, 0.18 [95% CI,-2.02 to 2.38]; P=0.87, I2=49%; standardized mean difference, 1.22 [95% CI, -0.45 to 2.88]; P=0.15, I2=68%). Overall, risk of bias was moderate-to-high and quality of evidence (Grading of Recommendations Assessment, Development and Evaluation) was very low, reflecting the observational nature of the data. CONCLUSIONS: Accepting the observed limitations, current evidence does not suggest a harmful effect of AHT on CBF. Concerns over CBF should not preclude treatment of hypertension.

Oral antiplatelet therapy for acute ischaemic stroke.

BACKGROUND: In people with acute ischaemic stroke, platelets become activated and can cause blood clots to form and block an artery in the brain, resulting in damage to part of the brain. Such damage gives rise to the symptoms of stroke. Antiplatelet therapy might reduce the volume of brain damaged by ischaemia and also reduce the risk of early recurrent ischaemic stroke, thereby reducing the risk of early death and improving long-term outcomes in survivors. However, antiplatelet therapy might also increase the risk of fatal or disabling intracranial haemorrhage. OBJECTIVES: To assess the efficacy and safety of immediate oral antiplatelet therapy (i.e. started as soon as possible and no later than two weeks after stroke onset) in people with acute presumed ischaemic stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, and two trials registers, and performed forward reference/cited reference searching in August 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing oral antiplatelet therapy (started within 14 days of the stroke) with control in people with definite or presumed ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria and assessed trial quality. For the included trials, they extracted and cross-checked the data. They assessed risk of bias of each study using the Risk of Bias 1 (RoB1) tool and overall certainty of the evidence for each outcome using the GRADE approach. MAIN RESULTS: We included 11 studies involving 42,226 participants. Three new trials have been added since the last update (743 participants). As per the previous version of this review, two trials testing aspirin 160 mg to 300 mg once daily, started within 48 hours of onset, contributed 96% of the data. The risk of bias was low. The maximum follow-up was six months. With treatment, there was a decrease in death or dependency at the end of follow-up (odds ratio (OR) 0.95, 95% confidence interval (CI) 0.91 to 0.99; 7 RCTs, 42,034 participants; moderate-certainty evidence). For every 1000 people treated with aspirin, 13 people would avoid death or dependency (number needed to treat for an additional beneficial outcome 79). AUTHORS' CONCLUSIONS: Antiplatelet therapy with aspirin 160 mg to 300 mg daily, given orally (or by nasogastric tube or per rectum in people who cannot swallow) and started within 48 hours of onset of presumed ischaemic stroke, significantly decreased death and dependency, and reduced the risk of early recurrent ischaemic stroke without a major risk of early haemorrhagic complications; long-term outcomes were improved.

Age-related differences in cerebrovascular responses to cognitive stimulation using a novel method.

Aging is associated with a number of alterations to cerebrovascular function. We aimed to investigate the effect of age on cerebrovascular responses to cognitive stimulation using an objective two-parameter method.Previously derived from a large data-set (135 healthy participants) were applied to a task-activated dataset of 69 healthy participants in five different task conditions. Cumulative response rate (CRR) was calculated as the sum of responses across tasks and hemispheres.There was a significant effect of age (adjusted odds ratio: 1.02 (95% confidence interval: 1.01, 1.04), p = 0.016). There was also a significant effect of task (p = 0.002), but there was no significant interaction between age and task (p = 0.37). Increasing age was associated with increased CRR (adjusted odds ratio: 1.04 (95% confidence interval: 1.01, 1.07), p = 0.009).Using an objective two-parameter method, healthy older adults had increased cerebrovascular responses to cognitive testing.

The Cognition and Flow Study: A Feasibility Randomized Controlled Trial of the Effects of Cognitive Training on Cerebral Blood Flow.

BACKGROUND: Cognitive training (CT) has demonstrated benefits for healthy older adults (HG) and mild cognitive impairment (MCI), but the effects on vascular function are unknown. OBJECTIVE: This is a feasibility trial investigating the effects of CT on cerebral blood flow velocity (CBFv). METHODS: Twenty HG, 24 with Alzheimer's disease (AD), and 12 with MCI were randomized to 12 weeks of multi-domain CT or control. Outcomes included: cognition (Addenbrooke's Cognitive Examination III), mood, quality of life (QoL), physical, and neurovascular function (transcranial Doppler ultrasonography measured task activation of CBFv responses). Data are presented as mean difference (MD) and 95% confidence interval (CI). RESULTS: 47 participants completed the trial. There were three dropouts from the training arm in the AD group, and one in the HG group. The intervention was acceptable and feasible to the majority of participants with a high completion rate (89%). The dropout rate was higher among participants with dementia. Few changes were identified on secondary analyses, but QoL was significantly improved in HG post-training (MD: 4.83 [95% CI: 1.13, 8.54]). CBFv response rate was not significantly different in HG (MD: 1.84 [95% CI: -4.81, 1.12]), but a significant increase was seen in the patient group (MD: 1.79 [95% CI: 0.005, 3.58]), requiring sample sizes of 56 and 84 participants respectively for a fully-powered trial. CONCLUSION: A 12-week CT program was acceptable and feasible in HG, AD, and MCI. CT may be associated with alterations in vascular physiology which require further investigation in an appropriately powered randomized controlled trial.

Plasma and cerebrospinal fluid ABeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting.

BACKGROUND: Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. OBJECTIVES: To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. SEARCH METHODS: We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. SELECTION CRITERIA: We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. DATA COLLECTION AND ANALYSIS: Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. MAIN RESULTS: We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. AUTHORS' CONCLUSIONS: Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.

The Interaction of Dynamic Cerebral Autoregulation and Neurovascular Coupling in Cognitive Impairment.

BACKGROUND: Dynamic cerebral autoregulation (dCA) remains intact in both ageing and dementia, but studies of neurovascular coupling (NVC) have produced mixed findings. OBJECTIVE: We investigated the effects of task-activation on dCA in healthy older adults (HOA), and patients with mild cognitive impairment (MCI) and Alzheimer's Disease (AD). METHODS: Resting and task-activated data from thirty HOA, twenty-two MCI, and thirty-four AD were extracted from a database. The autoregulation index (ARI) was determined at rest and during five cognitive tasks from transfer function analysis. NVC responses were present where group-specific thresholds of cross-correlation peak function and variance ratio were exceeded. Cumulative response rate (CRR) was the total number of positive responses across five tasks and two hemispheres. RESULTS: ARI differed between groups in dominant (p=0.012) and non-dominant (p=0.042) hemispheres at rest but not during task-activation (p=0.33). ARI decreased during language and memory tasks in HOA (p=0.002) but not in MCI or AD (p=0.40). There was a significant positive correlation between baseline ARI and CRR in all groups (r=0.26, p=0.018), but not within sub-groups. CONCLUSION: dCA efficiency was reduced in task-activation in healthy but not cognitively impaired participants. These results indicate differences in neurovascular processing in healthy older adults relative to cognitively impaired individuals.

An objective method to identify non-responders in neurovascular coupling testing.

BACKGROUND: Neurovascular coupling (NVC) can be assessed using transcranial Doppler (TCD) measured task-activation of cerebral blood flow velocity (CBFv). However, not all individuals show consistent responses. The aim of this study was to develop a robust, objective, method to identify non-responders to task-activation. NEW METHOD: Using five-minute seated resting (non-stimulated), bilateral CBFv data from 135 healthy participants, the cross-correlation function peak (CCF) between the population coherent average and each individual was obtained for a randomly selected segment of data (40 s) for both hemispheres (n = 270). The variance ratio (VR) was calculated by comparing the variance in CBFv data pre- and post-random mark. The 90th percentile for non-stimulated data was used to determine the upper confidence limit of normal variation in the CCF peak value (0.53), and VR (2.59). These criteria were then applied to task-activated CBFv from 69 healthy participants for five cognitive tasks (attention, verbal fluency, language, visuospatial, memory). RESULTS: Data were accepted as responders if either CCF ≥ 0.53 or VR ≥ 2.59. The number of cases accepted as responders for each task were as follows: attention, 54-59 (78-86 %); verbal fluency, 42-48 (60-70 %); language, 51-53 (74-77 %); visuospatial, 54 (78 %); memory, 40-47 (58-68 %). COMPARISON WITH EXISTING METHOD: Currently, there are no objective criteria for the identification of non-responders in studies of NVC. This is a new method to objectively classify non-responders to task-activation. CONCLUSIONS: Using a large sample of resting CBFv data, we have set objective criteria to differentiate between responders and non-responders in task activation protocols.